Emily S. Gorell

Safety and Wound Outcomes Following Genetically Corrected Autologous Epidermal Grafts in Patients With Recessive Dystrophic Epidermolysis Bullosa

Importance Recessive dystrophic epidermolysis bullosa (RDEB) is a devastating, often fatal, inherited blistering disorder caused by mutations in the COL7A1 gene encoding type VII collagen. Support and palliation are the only current therapies. Objective To evaluate the safety and wound outcomes following genetically corrected autologous epidermal grafts in patients with RDEB. Design, Setting, and Participants Single-center phase 1 clinical trial conducted in the United States of 4 patients with severe RDEB with a measured area of wounds suitable for grafting of at least 100 cm2. Patients with undetectable type VII collagen keratinocyte expression were excluded. Interventions Autologous keratinocytes isolated from biopsy samples collected from 4 patients with RDEB were transduced with good manufacturing practice-grade retrovirus carrying full-length human COL7A1 and assembled into epidermal sheet grafts. Type VII collagen gene-corrected grafts (approximately 35 cm2) were transplanted onto 6 wounds in each of the patients (n = 24 grafts). Main Outcomes and Measures The primary safety outcomes were recombination competent retrovirus, cancer, and autoimmune reaction. Molecular correction was assessed as type VII collagen expression measured by immunofluorescence and immunoelectron microscopy. Wound healing was assessed using serial photographs taken at 3, 6, and 12 months after grafting. Results The 4 patients (mean age, 23 years [range, 18-32 years]) were all male with an estimated body surface area affected with RDEB of 4% to 30%. All 24 grafts were well tolerated without serious adverse events. Type VII collagen expression at the dermal-epidermal junction was demonstrated on the graft sites by immunofluorescence microscopy in 9 of 10 biopsy samples (90%) at 3 months, in 8 of 12 samples (66%) at 6 months, and in 5 of 12 samples (42%) at 12 months, including correct type VII collagen localization to anchoring fibrils. Wounds with recombinant type VII collagen graft sites displayed 75% or greater healing at 3 months (21 intact graft sites of 24 wound sites; 87%), 6 months (16/24; 67%), and 12 months (12/24; 50%) compared with baseline wound sites. Conclusions and Relevance In this preliminary study of 4 patients with RDEB, there was wound healing in some type VII collagen gene-corrected grafts, but the response was variable among patients and among grafted sites and generally declined over 1 year. Long-term follow-up is necessary for these patients, and controlled trials are needed with a broader range of patients to better understand the potential long-term efficacy of genetically corrected autologous epidermal grafts. Trial Registration clinicaltrials.gov Identifier: NCT01263379.

A Two-Year, Double-Blind, Randomized Placebo-Controlled Trial of Oral Green Tea Polyphenols on the Long-Term Clinical and Histologic Appearance of Photoaging Skin

BACKGROUND Green tea polyphenols (GTPs) have significant antioxidant and antiinflammatory activities, and prior short‐term studies suggest that these compounds may improve photoaging skin. OBJECTIVES To evaluate the long‐term effects of oral GTPs on the clinical and histologic characteristics of photoaging skin. MATERIALS AND METHODS Double‐blind, placebo‐controlled trial of 56 women aged 25 to 75 randomized to 250 mg GTPs or placebo twice daily for 2 years. A blinded dermatologist scored the appearance of photodamaged facial skin at 0, 6, 12, and 24 months. A blinded dermatopathologist scored the histologic characteristics of sun‐exposed arm skin at 0 and 24 months. RESULTS Clinical assessment of facial skin revealed that the GTP group had significant improvement in overall solar damage at 6 months (p=.02) and significant improvement in erythema and telangiectasias at 12 months (p=.02). The placebo group did not have significant improvements in these parameters at 6 months or 12 months. There were no statistically significant differences in other photoaging parameters at 6, 12, or 24 months in the GTP or placebo groups. Histopathologic analysis of sunexposed arm skin showed no statistically significant difference in photoaging parameters in the GTP group or the placebo group at 24 months. CONCLUSIONS Long‐term supplementation with oral GTPs was not superior to placebo in improving clinical or histologic photoaging parameters after 24 months of use. Funding and materials for this study were provided by Nu Skin, Provo, Utah. Dale Kern is an employee of Nu Skin International.

The integrity of the dermatology National Resident Matching Program: results of a national study.

BACKGROUND National Resident Matching Program (NRMP) policy outlines the conduct expected by both program directors and residency applicants. However, recent studies and personal experiences have introduced the possibility that NRMP policy is violated during the residency application process. OBJECTIVE To investigate the communications that occur between dermatology applicants and dermatology programs during the residency application process. METHODS From April to July 2009, we surveyed 2009 Stanford dermatology applicants, current US dermatology residents, and US dermatology program directors. The survey was anonymous and available online. The main outcome measures were the frequency and incidence of dermatology NRMP policy violations. RESULTS Thirty-one percent of Stanford applicants and 19% of US dermatology residents felt pressured to reveal to programs how they ranked them before match day. Seventeen percent of Stanford applicants and 14% of US dermatology residents witnessed behavior that made them feel uncomfortable or that they thought was a possible ethical infraction of NRMP policy. LIMITATIONS Response rates were as follows: 43% of Stanford applicants, 46% of residents, and 61% of program directors. CONCLUSIONS Our data suggest that some dermatology program directors violate NRMP policy during their communications with applicants. The most widespread violation is pressuring applicants into revealing how they intend to rank programs. Other violations include apparent sexual discrimination and reserving NRMP positions for preselected applicants. Additional studies should be done in order to determine the incidence of dermatology applicants violating NRMP policy.

Adoption of Western Culture by Californian Asian Americans: Attitudes and Practices Promoting Sun Exposure

OBJECTIVE To investigate whether the adoption of Western culture is associated with attitudes and practices promoting sun exposure among Asian Americans. DESIGN Survey conducted from November 28, 2007, to January 28, 2008. SETTING Primarily northern California community groups via online survey. PARTICIPANTS Adult volunteers who self-identified as Asian American. MAIN OUTCOME MEASURES Results based on 546 questionnaires returned. RESULTS The overall response rate was 74.4%. Multivariate regression analysis controlling for age and skin type showed that westernization (as determined by generation in the United States, location raised, or self-rated acculturation) was associated with attitudes and behaviors promoting sun exposure (including the belief that having a tan is attractive, negative attitudes toward use of sunscreen and sun protective clothing, and increased weekend sun exposure, lying out to get a tan, and tanning bed use) at a level of P < .05. CONCLUSIONS Our data suggest that adoption of Western culture may be associated with attitudes and behaviors promoting sun exposure among Asian Americans. This group should be targeted by dermatologists for increased education regarding sun protection, solar damage, and skin cancer prevention and detection.

Gene Therapy for Skin Diseases

The skin possesses qualities that make it desirable for gene therapy, and studies have focused on gene therapy for multiple cutaneous diseases. Gene therapy uses a vector to introduce genetic material into cells to alter gene expression, negating a pathological process. This can be accomplished with a variety of viral vectors or nonviral administrations. Although results are promising, there are several potential pitfalls that must be addressed to improve the safety profile to make gene therapy widely available clinically.

A follow-up survey of the integrity of the dermatology National Resident Matching Program

BACKGROUND Our groups 2009 study of the integrity of the dermatology match revealed that some dermatology program directors violated National Resident Matching Program (NRMP) policy during their communications with applicants. Our groups article concluded with recommendations to change this behavior. OBJECTIVE We repeated a survey of dermatology applicants to understand if dermatology program personnel behavior has changed since our groups 2009 study of the dermatology match. METHODS We surveyed 2011 applicants to Department of Dermatology, Stanford University, Palo Alto, CA. The survey was anonymous and available online. RESULTS Of applicants, 14% were asked to reveal how they intended to rank a program before match day. Of applicants, 32% felt pressured to reveal how they intended to rank programs. Of applicants, 90% were asked about interviews at other programs. Of applicants, 44% were asked about their marital status and 19% were asked if they had children or intended to have children. LIMITATIONS The response rate for applicants was 53%. CONCLUSION Although our previous study increased knowledge about the problems within the dermatology match, dermatology program personnel continue to violate NRMP policy. The most widespread violations are asking applicants where they will interview, asking applicants if they are married, and pressuring applicants to reveal how they intend to rank programs. We continue to recommend that programs avoid postinterview contact, and recommend that the NRMP create training videos for applicants and interviewers.

Characterization of patients with dystrophic epidermolysis bullosa for collagen VII therapy

Dystrophic EB (DEB) is a blistering skin disease caused by mutations in the gene (COL7A1) encoding type VII collagen (C7). DEB can be inherited by either dominant (DDEB) or recessive (RDEB) mechanisms. RDEB results in severe wounds and scarring, as well as extracutaneous manifestations such as esophageal strictures, chronic anemia, and pseudosyndactyly. DDEB is generally a milder form, with fewer and less severe blisters.(1)

Successful Investigational New Drug Preparation without Reinventing the Wheel

The biotech industry is the usual venue of new drug development, with costs estimated between

Diagnosis of pilomatricoma using an otoscope.

500 million and

Differential effects of dietary supplements on metabolomic profile of smokers versus non-smokers.

2 billion per drug developed (Adams and Brantner, 2006). Occasionally, members of an academic medical community may choose to develop a new drug within their own institution because they are focused on an orphan disease and/or their new therapy may lack a successful financial model. The Dermatology Department at Stanford University School of Medicine has focused on creating a successful treatment for epidermolysis bullosa since 1988. Support for this process has come from philanthropy (http://www.ebkids.org) as well as federal and state funding.